The TaqI A DRD2 polymorphism in type II alcohol dependence: a marker of age at onset or of a familial disease?

Cloninger's type II is a severe, early-onset, male-limited, and genetically influenced, impulsive form of alcoholism. Significant association has been reported between the A1 allele of the D2 dopamine receptor (DRD2) gene, substance misuse and personality traits of impulsivity and novelty seeking. We assessed the association between the TaqI A DRD2 gene polymorphism with Cloninger's typology and family history of alcohol abuse, which is thought to be more frequent in type II alcoholics. Fifty-one male alcohol-dependent patients were discriminated between type I and type II according to age at onset of alcohol-related problems and interviewed about family history of alcoholism. The associations between DRD2 (A1 or A2 alleles), family history, and typology were assessed by Pearson's chi-square test. Although typology was not associated with the studied polymorphism, a higher rate of general family history of alcohol abuse was still observed in type II patients (chi(2)(1)=4.53; P=.033). Furthermore, the A1 allele of the DRD2 was significantly associated with paternal history of alcoholism (chi(2)(1)=4.66; P=.031) and male, first-degree, collateral history of alcoholism (chi(2)(1)=4.40; P=.036). Age at onset of alcohol-related problems as main discriminator between type I and type II alcohol dependence does not seem to be associated by the TaqI A DRD2 polymorphism. However, the A1 allele of the DRD2 may be a marker of male familial alcoholism, which has been associated with type II alcohol dependence.

The short allele of the serotonin transporter promoter polymorphism influences relapse in alcohol dependence.

AIMS: The short (S) allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR) contributes to the risk of alcohol dependence and co-occurring clinical features. We studied the putative link between this allele and relapse. METHODS: 48 alcohol-dependent male patients were recruited and genotyped for the 5-HTTLPR. Relapse to alcohol drinking was monitored during 3 months after standardized withdrawal. RESULTS: The S allele was significantly associated with relapse (p = 0.008) while no other factor that was measured played a significant role. CONCLUSIONS: The S allele of the 5-HTTLPR polymorphism may influence the risk of relapse in abstinent alcohol-dependent patients, possibly through intermediate phenotypes.

Vasopressin-neurophysin and DST in major depression: relationship with suicidal behavior.

The purpose of the present study was to assess if AVP-neurophysin is associated with hypercortisolemia and suicidal behaviour in depressed patients. The study included 28 patients subgrouped into suicide attempters (n=13) and nonattempters (n=15). We assessed basal AVP-neurophysins concentrations and post-dexamethasone (DST) cortisol levels. Concentrations of AVP-neurophysins did not differ between DST suppressors and nonsuppressors: 0.29+/-0.13 ng/ml vs 0.36+/-0.21 ng/ml, (F=1.1, df=1, 27, p=0.30). Suicide attempters did not differ from nonattempters for AVP-neurophysins levels. Our results fail to support a role of AVP in the early cortisol escape.

Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices.

BACKGROUND/AIMS: Periodic endoscopic screening for oesophageal varices is recommended in patients with cirrhosis, but might be limited to a subgroup of patients if a simple non-invasive test was available to select those at risk of bleeding. METHODS: We studied in 165 patients with cirrhosis the relation between the presence of oesophageal varices assessed by endoscopy, and liver stiffness measurement by Fibroscan, a non-invasive parameter related to liver fibrosis. The results were compared to those of other parameters reflecting portal hypertension, splenic size, platelet count, and platelet count/spleen size ratio. RESULTS: Liver stiffness measurement was correlated to the grade of oesophageal varices (r = 0.6, p < 0.0001). AUROC values of liver stiffness measurement were 0.84 (95% CI: 0.78-0.90) for the presence of oesophageal varices and 0.83 (0.76-0.89) for varices grade > or = II. Liver stiffness measurement value < 19 kPa was highly predictive of the absence of oesophageal varices grade > or = II (Se: 84%, PPV: 47%, NPV: 93%). CONCLUSIONS: Liver stiffness measurement allows to predict the presence of large oesophageal varices in patients with cirrhosis, and may help to select patients for endoscopic screening.

5-Hydroxytryptamine 1A receptors, major depression, and suicidal behavior.

BACKGROUND: Several lines of evidence suggest a clear relationship between serotonin (5-hydroxytryptamine, 5-HT) hypoactivity and suicidal behavior across several psychiatric diagnoses. Few data are available, however, regarding the possible specific role of 5-HT1A receptors in the biology of suicidality. Therefore, the aim of our study was to use a neuroendocrine strategy to test the hypothesis of a role for 5-HT1A receptors in the biology of suicidal behavior. METHODS: Hormonal (adrenocorticotropic hormone [ACTH], cortisol, prolactin [PRL]) and temperature responses after administration of flesinoxan, a highly potent and selective 5-HT1A receptor full agonist, were assessed in 40 inpatients with major depression, divided into two subgroups (20 suicide attempters and 20 nonattempters), compared with 20 normal control subjects matched for gender and age. RESULTS: Compared with nonattempters, suicide attempters exhibited significantly lower PRL (p = .01), cortisol (p = .014), and temperature (p = .0002) responses. Prolactin (p = .007), cortisol (p = .04), and temperature (p = .00003) responses were also decreased in suicide attempters compared with normal control subjects. In contrast, we did not observe any significant differences in hormonal or temperature responses to flesinoxan between depressed patients without a history of suicide attempt and normal control subjects. CONCLUSIONS: The present study tends to confirm the role of 5-HT and more specifically 5-HT1A receptors in the biology of suicidal behavior in major depression.

Polymorphisms in the CYP 2D6 gene: association with plasma concentrations of fluoxetine and paroxetine.

Most antidepressants are metabolized by cytochrome P450 (CYP) 2D6, and it is well known that there may be significant interindividual variation in the capacity to metabolize xenobiotics. About 7 to 10% of whites are poor metabolisers (PM), and, on the contrary, about 5% are ultrarapid metabolizers (UM), inducing very different rates in the transformation of antidepressants extensively metabolized by CYP 2D6. CYP 2D6 polymorphism can be a potential risk factor for the development of side effects or a reason for the poor efficacy of the treatment. Various probe drugs may be used for phenotyping CYP 2D6, but genotyping is now available using leukocyte DNA and is independent of concomitant drug use. In this study, we used PCR-based methods for the identification of CYP 2D6 genotypes in 49 patients receiving standard doses of fluoxetine or paroxetine and found that plasma concentration of the antidepressant drugs was significantly correlated with genetic status. In one patient who displayed CYP 2D6 gene duplication (UM), paroxetine plasma concentration was extremely low. In PM fluoxetine-treated patients, drug plasma concentration was significantly higher than that seen in extensive metabolizers.

Event-related potentials to emotional and neutral stimuli in alcoholism.

Several studies have demonstrated that the emotional value of stimuli affects P300 amplitude. In the present study, the influence of alcohol-related stimuli in alcoholic patients was investigated. Subjects were 10 alcoholic inpatients (3 female) and 10 age- and sex-matched controls. Eight alcohol-related and 8 neutral words served as stimuli in a visual oddball paradigm. Acohol-related words were targets (48 stimuli, 33%) and neutral words were standard stimuli (96 stimuli, 66%). Results showed that P300 amplitude for targets did not differ significantly between the two groups. However, P300 latency for targets as well as reaction time were significantly shorter in male alcoholic patients. In contrast, P300 latency was increased in female alcoholic patients but reaction time did not differ. These results suggest that male alcoholics process information linked to alcohol cues more rapidly than neutral cues, probably because a specific semantic network is activated in these patients. The decreased reaction time confirms the impulsive behavior frequently found in male alcoholism, as it has been described in type II alcoholism. Besides, the results imply that information processing was delayed in female alcoholic patients. Therefore this study demonstrates a gender-dependent impact of alcohol-related stimuli on information processing.

Catecholamine and HPA axis dysfunction in depression: relationship with suicidal behavior.

A large body of evidence suggests a potential role for catecholaminergic function as a possible biological factor in the control of suicidal behavior. Recently, we have used a neuroendocrine strategy to study dopaminergic and noradrenergic activities in depressed suicide attempters. However, some problems are associated with the use of growth hormone (GH) response to catecholaminergic challenge, because GH release could be decreased by a direct effect of corticosteroids at the pituitary level. Therefore, the purpose of the present study was to assess GH response to both apomorphine, a dopaminergic agonist, and clonidine, an alpha2-adrenergic agonist, according to the dexamethasone suppression test (DST) status in a sample of 20 major depressed inpatients with a history of suicide attempt compared with nonattempters. Our results tended to show that hypercortisolemia as assessed by post-DST cortisol values did not inhibit GH response to apomorphine or clonidine, suggesting that hypothalamo-pituitary-adrenal axis overactivity does not explain the impaired GH response to apomorphine in major depressed patients with a history of suicide attempt.

Hormonal and temperature responses to the 5-HT1A receptor agonist flesinoxan in normal volunteers.

RATIONALE: Flesinoxan is a highly potent and selective 5-HT(1A) agonist and appears to be a potentially interesting neuroendocrine serotonergic probe. OBJECTIVES: We assessed hormonal (ACTH, cortisol, prolactin and growth hormone) and temperature responses to flesinoxan in normal volunteers. METHODS: In a double-blind placebo-controlled study, single doses of 0.5 mg and 1 mg were injected over 10 min into 12 healthy male volunteers at 1-week intervals. Temperature and hormonal responses were measured at times -30, 0, 15, 30, 60, 90, and 120 min. RESULTS: Flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. Tolerance to flesinoxan was excellent. CONCLUSIONS: These results showed the role of 5-HT(1A) mechanisms in the PRL, ACTH, cortisol, GH, and temperature responses to flesinoxan. In the present study, flesinoxan appears a very promising serotonergic neuroendocrine probe.